The high affinity receptor for IgE on mast cells & basophils (Fc(epsilon)RI) plays a central role in immediate hypersensitivity reactions. Reaction of receptor-bound IgE with polyvalent antigen clusters the receptors & this stimulates cellular secretion of both preformed & newly synthesized mediators of inflammation. Our studies focus on the molecular mechanisms by which aggregation of the receptors generate these cellular responses. The similarity of Fc(epsilon)RI to other receptors of the immune system (e.g. the clonotypic receptors on T & B lymphocytes), make it likely that the significance of such studies extends beyond the IgE/mast cell system. During the past year, our principal progress was in two areas: 1) Completing the first phase of our studies on the association between a tyrosine kinase and the receptor. Using either gentle isolation procedures or chemical crosslinking, we found convincing evidence for the following mechanism by which the topological change induced by aggregation of the receptors is converted into a biochemical signal: a) Some unaggregated receptors are constitutively associated with the src-like tyrosine kinase--p55/56lyn in the case of receptors in the rat "RBL" cell-line with which we work. b) Aggregation of receptors in effect induces the formation of enzyme-substrate complexes so that the kinase on one receptor can (trans)phosphorylate other receptors newly approximated to it. c) Such phosphorylated receptors "recruit" additional kinase thereby initiating the biochemical cascade. 2) Further analysis on the dynamics of signal transduction in relation to aggregation of the receptors in vivo. Quantitative analysis of the relationship of aggregation to phosphorylation of receptor tyrosines revealed a discrepancy that cannot be accommodated by any simple model. The data suggest that not only the amount but also the rate of aggregation may influence the cellular response. These results have general implications on the role of ligand-receptor interactions in initiating alternative cellular responses.